Estrogen receptor beta variants and methods of detection thereof

Abstract

The present invention is based on sequencing genomic DNA from human chromosome 6 and cDNAs to define the genomic structure of estrogen receptor beta genes and novel polymorphism in the estrogen receptor gene/protein. Such polymorphism can lead to a variety of disorders that are mediated/modulated by a variant estrogen receptor, such as a susceptibility to cancer, osteoporosis, cardiovascular disorder, etc. Based on this sequencing approach, the present invention provides genomic nucleotide sequences, CDNA sequences, amino acid sequences and sequence polymorphism in the ESR-beta genes, methods of detecting these sequences/polymorphism in a sample, methods of determining a risk of having or developing a disorder mediated by a variant estrogen receptor and methods of screening for compounds used to treat disorders mediated by a variant estrogen receptor.

Description

[0001] The present application claims priority to provisional application U.S. Ser. No. 60 / 183,755, filed Feb. 22, 2000 (Atty. Docket CL000280-PROV).[0002] The present invention is in the field of disease detection and therapy. The present invention specifically provides the identification of previously unknown nucleic acid / amino acid polymorphisms within the estrogen receptor beta gene (ESR-beta) and the genomic sequence of this gene for use in the development of diagnostics and therapies for diseases and disorders mediated / modulated by the estrogen receptor.BACKGROUND OFF THE INVENTIONEstrogen Receptor[0003] The human estrogen receptor beta belongs to the nuclear hormone receptor family. Nuclear hormone receptors are a family of hormone-activated transcription factors that can initiate or enhance the transcription of genes containing specific hormone response elements.[0004] The ER protein consists of 595 amino acids with a molecular weight of 66 kDa, 8 transcribed exons, with six...

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Benefits of technology

0018] For postmenopausal women without frank disease, estrogen replacement therapy appears to have a beneficial effect when one considers the magnitude, consistency, and biological pl

Problems solved by technology

However, a "healthy woman selection bias" is present in these studies and potentially may confound these results (estrogen takers have better weight control, exercise more, and smoke less than women who are not prescribed estrogen).

Estrogen replacement therapy is not without risk.

Controversy continues over whether estrogen replacement increases the risk of breast cancer, but some studies indicate risk is elevated by as much as 30%.

Based on these results, hormone replacement therapy is not recommended for secondary prevention of heart disease.

While the study mentioned above indicated that estrogens did not alleviate RA symptoms, another study concluded that adjuvant estrogen therapy did not even improve the symptoms.

Osteophorosis is a metabolic bone disorder that leads to bone fragility and subsequent risk of fracture.

All of these factors, with the exception of family history, have been shown to be directly associated with lifetime exposure to estrogen, increased hormone exposure being associated with increased risk of developing breast cancer.

In addition to these somatic mutations, some studies have pointed to a possible association between inherited DNA sequence changes and the development of breast cancer, but these studies are also controversial.

Although it remains somewhat controversial, studies suggest that use of tamoxifen may increase the chance of developing endometrial cancer.

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